POS1043 SKELETAL MUSCLE PGC1Α1 PREVENTS ARTHRITIS-INDUCED CAPILLARY RAREFACTION AND IMPAIRED GLUCOSE UPTAKE
Authors: B. Jude, A. Chibalin, S. Ducommun, J. Zierath, F. Von Walden, J. Ruas, A. Krook, J. Lanner
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease with prevalent musculoskeletal complications (Steinz et al., 2019; Steinz, Santos-Alves, &amp; Lanner, 2020), including metabolic disturbances. Patients with RA have a higher risk of developing type 2 diabetes (T2D) than the general population, however, the causality between RA and T2D is unknown. Skeletal muscle is essential for locomotor activity and the primary site for postprandial glucose disposal. <h3>Objectives</h3> Here we utilized a mouse model of arthritis and mice with chronic elevated expression of the transcriptional co-activator PGC1α1 to elucidate metabolic and functional alterations in skeletal muscle induced by chronic inflammation. <h3>Methods</h3> Arthritis was induced by complete Freund's adjuvant (CFA, ankle injection) in female wildtype or muscle-specific PGC-1α1 transgenic (MCK-PGC1α1) mice. Glucose uptake (<i>in vivo</i> and ex <i>vivo</i>), immunofluorescence staining, and immunoblotting were assessed 14 days post-CFA injection. Gene expression was analyzed 3 days after CFA induction. <h3>Results</h3> <i>In vivo</i> glucose uptake was reduced by 50-80% in limb muscle (extensor digitorum longus, tibialis anterior, soleus) of mice with arthritis as compared with control mice. Despite this, GLUT4 abundance and membrane translocation were enhanced by ~160% and ~70%, respectively, in limb muscle afflicted by CFA as compared with control. However, no difference was observed in <i>ex vivo</i> glucose uptake between the two groups, suggesting the reduction in glucose uptake was due to an alteration in muscle blood perfusion. Expression of angiogenesis-associated genes, including PGC1α (total and α1 isoforms), VEGF (A and B), and ERR (α and γ) was decreased by 50-70% in muscles afflicted by CFA, which was accompanied by a 25% reduction in muscle capillary density (capillary rarefaction). Muscle specific chronic elevation of PGC1α1 prevented the increase in GLUT4 abundance and capillary rarefaction induced by arthritis. <h3>Conclusion</h3> Induction of arthritis leads to reduced muscle capillary rarefaction and glucose uptake, which can advance the risk of developing metabolic disease. Strikingly, this pathophysiological development can be corrected by PGC-1α1. <h3>References</h3> [1] Steinz, M. M., Persson, M., Aresh, B., Olsson, K., Cheng, A. J., Ahlstrand, E.,... Lanner, J. T. <b>(2019</b>). Oxidative hotspots on actin promote skeletal muscle weakness in rheumatoid arthritis. JCI Insight, Mar 28;5(9):e126347. doi:10.1172/jci.insight.126347 [2] Steinz, M. M., Santos-Alves, E., &amp; Lanner, J. T. <b>(2020</b>). Skeletal muscle redox signaling in rheumatoid arthritis. Clin Sci, Nov 13;134(21):2835-2850. doi:10.1042/cs20190728 <h3>Acknowledgements</h3> This study has been supported by The Swedish Research Council, The Promobilia foundation, The Swedish Rheumatism foundation, and The Royal King Gustaf V's memorial foundatio.n. <h3>Disclosure of Interests</h3> None Declared.